Synthesis of 5-Methyl-2-(Pyridin-3-yl)-6-(Trifluoromethyl)Pyrimidin-4(3H)-One (22, 0497401)

Et₃N (0.9 mL, 6.5 mmol) was added to a solution of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (250 mg, 1.3 mmol) and nicotinimidamide hydrochloride (198 mg, 1.3 mmol) in EtOH (10 mL) at RT. The reaction mixture was then heated at 110°C for 5 h and monitored by TLC analysis (5% MeOH–DCM) until completion. The reaction mixture was evaporated to dryness and poured to ice cooled water (20 mL). It was extracted with DCM (3 × 20 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude was further purified by column chromatography on silica gel (60–120 mesh) using 20% EtOAc-hexane as eluent to afford 19 as a white solid (150 mg, 58%). The crude was purified by flash chromatography on silica gel (60–120 mesh) using 19% EtOAc-hexane as eluent to afford 23 as a white solid (140 mg, 43%). M.P. 213–215°C. ¹H NMR (400 MHz, DMSO-d₆): δ 13.48 (s, 1H), 9.22 (d, J = 1.4 Hz, 1H), 8.74–8.76 (m, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.56–7.60 (m, 1H), 2.16 (d, J = 2.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 164.1, 153.9, 152.2, 148.7, 146.8 (q, J = 24.8 Hz), 135.4, 128.0, 123.9 (q, J = 275 Hz), 123.6, 122.6, 10.1. LCMS (ESI) m/z calculated for [C₁₁H₈F₃N₃O + H]⁺, 256.07; found 256.28.